1&#39;-(delta9(11)-5beta-androstene-3alpha-ol-17beta-yl)-3&#39;, 5&#39;, 8&#39;-trioxa bicyclo-(2, 2, 2)-octane and its carboxylic acid esters



United States Patent O ice 3,114,676

Paiented Dec. 17, 1963 1 2 3,114,676 The novel compounds of the invention have the formula 1-(A -5p-ANDR0STENE-3u-0L 1713 YL) 3',5,8- C1320 TRIQXA BICYCLO-(2,2,2)-OCTANE AND ITS CAR- \CH noxvuc ACID ESTERS 2 Daniel Bertin, Montrouge, and Lucien Nedelec, Clichyonto sous-Bois, France, assigncrs to Roussel-UCLAF, S.A., Paris, France, a corporation of France No Drawing. Filed Oct. 30, 1962, Ser. No. 234,232.

Claims priority, application France Nov. 3, 1961 R0 14 Claims. (Cl. 167-65) H I The invention relates to the novel androstene comwherein R is selected from the group consisting of hydropounds having the formula gen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms.

CHzO Examples of suitable organic carboxyhc acids having 15 1 to 7 carbon atoms to form the esters of Formula I are H CHzO aliphatic acids such as acetic acid, propionic acid, trimethy-l acetic acid, butyric acid, 4,4-dimethy1 pentancic acid, etc. and aromatic acids such as benzoic acid.

The process of the invention for the preparation of the compounds of Formula I comprises dehydrating a 30;,21-

H I diacyloxy-20-bis (acyloxymethyl) 5,8 pregnane-llfl-ol wherein R is selected from the group consisting of hydro wherein the acyl radical is derived from an organic cargen and an acyl radical of an organic carboxylic acid boxylic acid having 1 to 18 carbon atoms to form a having 1 to 7 carbon atoms. The invention also relates 30:,21 diacyloxy 2O bis (acyloxyrnethyl) M -55- to a novel process for the preparation of the androstenes pregnene, saponifying the latter under alkaline conditions of Formula I and to novel intermediates thereof. The to form 20-bis (hydroxymethyl)-A -5,B-pregnene-3a,

invention further relates to a novel method for the treat- 2l-diol, condensing the latter with a lower alkyl orthoment of vascular and visceral spasms. formate to form 1-(A -513-androstene-3a-ol-l7,8-yl)- The compounds of Formula I possess a spasmolytic 3,5,8-trioxa bicyclo-(2,2,2)-octane which may be esteriactivity accompanied with a dilatory activity on coronary tied with an organic carboxylic acid having 1 to 7 carbon blood vessels and a peripheric vasodilatory activity and atoms or a functional derivative thereof such as an acid can be used for the treatment of spasms of coronary halide or acid anhydride and recovering a compound of origin, spasms of the arterial or veinous system, of angina Formula I. of the chest and of asthma and bronchial spasms. A preferred mode of the process of the invention for It is an object of the invention to provide the novel the preparation of compounds of Formula I comprises products, 1-[A -5fi-androstene-3a-ol-l7fi-yl] 3',5',8'- dehydrating 3a,2l-diacetoxy-20-bis (acetoxymethyD-SB- trioxa bicycle [2,2,2] -octane and its carboxylic acid pregnane-llfl-ol in the presence of a dehydrating agent esters. such as perchloric acid in acetic acid or methane sulfonyl It is another object of the invention to provide a novel chloride and pyridine in dimethylformamide to form process for the preparation of the androstene compounds 3a,21 diacetoxy 20 bis (acetoxymethyl) M -55- of Formula I. pregnene, saponifying the latter in the presence of a con- It is a further object of the invention to provide novel centrated aqueous alkali metal hydroxide solution to form intermediates for the compounds of Formula I. 20 bis (hydroxymethyl)-A -5fi-pregnene-3a,2l-diol,

It is an additional object of the invention to provide a condensing the latter with ethyl orthoformate in the presnovel method of treating vascular and visceral spasms. ence of an acidic catalyst such as p'toluene sulfonic acid It is another object of the invention to provide novel to form l(A -5B androstene- 3a-ol-l7B-yl)-3',5',8-

compositions for the treatment of vascular and visceral trioxa bicyclo-(2,2,2)-octane which may be acylated with spasms. an organic carboxylic acid having 1 to 7 carbon atoms These and other objects and advantages of the invenor a functional derivative thereof and recovering a comtion will become obvious from the following detailed pound of Formula I. The reaction scheme is illustrated description. in Table I.

TABLE I GHzOAc CHzOAc no A ogonioac COH2OA0 W OHzOAC I \CH2OAC AU n l a s wherein R has the above definition and Ac is the acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

The novel compositions of the invention for the treatment of spasms of vascular and visceral origin are comprised of a compound having the formula CHzO wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms and a pharmaceutical carrier. The compositions may be in the form of injectable solutions, injectable suspensions, prepared in ampules, in multiple dose flacons and in the form of tablets and suppositories prepared in the usual manner.

The novel method of the invention for the treatment of spasms of vascular and visceral origin comprises administering an eliective amount of a compound having the formula where-in R is selected from the group consisting of hydro gen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms. The said compounds may be administered orally, rectally or t-ranscutaneously. The usual daily dose is to 50 mgm. per day in the adult depending upon the method of administration.

The 3a,21-diacyloxy-20-bis (acyloxymethyD-Sfi-preg- 113116-11 lfi-ols wherein the acyl radical is derived from an organic car-boxylic acid having 1 to 18 carbon atoms used as starting materials for the process of the invention may be prepared by condensing 3a-acetoxy-Sfl-androstane-11, 17-dione with ethyl cyanoacetate to form the ethyl ester of 3a-acetoxy-20-cyano-A -Sfl-pregnene-ll-one-Zl-oic acid, catalytica'lly hydrogenating the latter to form the ethyl ester of 3a-acetoxy 20 cyano-5;S-pregnane-1 1one-, 21-oic acid, simultaneously saponifying and hydrolyzing the latter under alkaline conditions to form 20-carboxy- S,B-pregnane-3a-ol-1l-one-21-oic acid, esterifying the latter with methanol in the presence of hydrochloric acid to form the methyl ester of 20 carbomethoxy-Sfl-pregnane- 3a-ol-11-one-21-oic acid, reacting the latter with 2,3-dihydropyran to :form the methyl ester of 306-(2'46t13hYd1'0- pyranyloxy) 20 carbomethoxy 5e pregnane-l l-one- 21-oic acid, reacting the sodium derivative of the latter with benzyloxy chloromethane to form the methyl ester of 3a-(2.-tetrahydropyranyloxy) 20 carbomethoxy-ZO- benzyloxymethyl 55 pregnane-l 1-one-21-oic acid, hydrolyzing the latter under acidic conditions to form the methyl ester of 20-carbomethoxy-20-benzyloxymethyl-5flpregnane-3a-0l-11-one-21-oic acid, reducing the latter with lithium aluminum hydride to form ZO-hydroxymethyl ZO-benzyloxymethyl-Sfl-pregnane-Ba,11 S,21-triol, subjecting the latter to catalytic hydrogenolysis to form 2l0bis-(hydroxymethyl)-5/8-pregnane 311,11 [3,21-triol and esterifyin g the latter with an organic carboxylic acid having 1 to 18 carbon atoms or a functional derivative there- 4 of to form 3a,21-diacyloxy-20-bis (acyloxymethyD-Sppregnane-l 1 5-01.

The organic carboxylic acid having 1 to 18 carbon atoms may be aliphatic, aromatic or cycloaliphat-ic. Examples of suitable organic carboxylic acids are alkanoic and alkenoic acids such as acetic acid, trimethyl acetic acid, propionic acid, 4,4-dimethyl pent'anoic acid, 10- undecanoic acid; cycloalkyl-alkanoic acids such as ,B-cyclopentyl propionic acid; aryl alkanoic acids such as phenyl propionic acid; cycloalkanoic acids such as hexahydrobenzoic acid and hexahydroterephthalic acid and phenyl carboxylic acids such as benzoic acid and 3,5- dinitrobenzoic acid.

In the following example there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 1 '-[A 5 8 Androstene 3a-OI-17/3-YIJ- 3 ',5 ,8-Tri0xa Bicyclo- [2,2,2]-0ctane and its Sat-Acetate STEP A.PREPARA'TION OF 3a,2l-DIACETOXY-20-BIS- (ACETOXYMETHYL) -A9(11)-513-PREGNENE 5.649 g. of 3a,2l-diacetoxy 20-bis-(acetoxymethyl)-5,8- pregnane-llfl-ol were dissolved in cc. of acetic acid. Then under agitation 1.7 cc. of 65% perchloric acid was added and the reaction mixture was allowed to stand for a period of about four hours in an atmosphere of nitrogen. Then the solution obtained was poured into 600 cc. of a mixture of water and ice and the aqueous solution was extracted several times with methylene chloride. The combined extracts were washed successively with water, with an aqueous solution containing 10% of sodium bicarbonate and with water, dried over magnesium sulfate and evaporated to dryness. Raw 3a,2l-diacetoxy- 20-bis-(acetoxymethyl)-A -5;8-pregnene was obtained which was used as such for the next stage of the synthesis. However, it could be purified by chromatography through magnesium silicate with elution by methylene chloride containing 1% of methanol.

This compound, which is soluble in alcohol, ether, acetone, benzene and chloroform, is not described in the literature.

STEP B.PREPARA'TION OF 20-BIS-(HYDROXY- METHYL)-A" -5fiPREGNENE-3a,21-DIOL 5.442g. of the product prepared in Step A were dissolved in 54 cc. of ethanol. The solution was heated to reflux and over a period of several minutes 8.15 cc. of concentrated sodium hydroxide solution and 11 cc. of water were added. The reaction mixture was maintained at reflux temperature under agitation for a period of about 20 minutes and then cc. of a mixture of water and ice were added. The precipitate formed was vacuum filtered, washed with water until the wash waters were neutral, and dried. The dried precipitate was triturated with dioxane and dried. 3.278 g. of ZO-bis-(hydroxymethyl)-A -5/8 pregnene 3a,21-di01 having a melting point of 266 C. and a specific rotation (c.=0.1% in ethanol) were obtained.

The product was very slightly soluble in acetone, alcohol and ether and insoluble in chloroform.

Analysis.C H O molecular weight=378.53. Calculated: C, 72.98%; H, 10.12%; 0, 16.91%. Found: C, 73.2%; H, 10.0%; 0, 17.3%.

This compound is not described in the literature.

STEP C.--PREPARATION OF 1-[A9(11)-5B-ANDROSTE-NE- 3a-OL-l7fl-YL] -3,5',8-TRIOXA BICYCLO [2,2,21-OCTANE 3.25 gm. of ZO-bis-(hydroxymethyl)-A -5;8-pregnene-3oc,21-di ol were suspended in a mixture of 4.4 cc. of dioxame and 65 mgm. of p-tol uene sullfonic acid. The suspension was subjected to agitation and 1.40 cc. of ethyl orthoformate were added in one amount at a temperature of 37-38 C. Then in 30 minutes another 2.80 cc. of the same compound were added. After 2 hours of reaction, the reaction mixture was allowed to cool until room temperature, then successively 1 cc. of pyridine and 5 cc. of an aqueous solution containing of sodium bicarbonate were added. The reaction mixture was diluted by slow addition of 50 cc. of water and agitated for a period of about one hour. The percipitate formed was vacuum filtered, Washed successively with water, with 50% alcohol, with alcohol and with isopropyl ether and dried. 2.69 g. of l'-(A -5fl-androstene-3aol-17fl-yl)-3',5,8'-trioxa bicyclo-(2,2,2)-octane were obtained, which was purified by recrystallization from ethanol. The product had a melting point of 255 C.

lThlS compound is a crystallized colorless product soluble in chloroform, slightly soluble in alcohol and ether.

It is not described in the literature.

84 mgm. of 1-(A -5fi-androstene-3or-ol-17/3-yl)- 3',5',8'-trioxa bicyclo-(2,2,2)-octane were placed in suspension at room temperature in 0.8 cc. of pyridine and 0.4 cc. of acetic acid anhydride. The reaction mixture was heated to about 40 C. in order to obtain dissolution. The mixture was then agitated for a period of about one hour and a half and then the solution obtained was allowed to stand at 2224 C. for a period of about two hours and minutes. Next, a mixture of water and ice was added and the crystalline precipitate which appeared was vacuum filtered, washed with water and dried. 90 mgm. of 1-(3a-acetoxy-A -5{3-androstone-17,8-yl)-3',5,8trio-xa bicyclo-(2,2,2)-octane having a melting point of 232 C. were obtained.

This compound was a crystallized colorless product, and was very soluble in chloroform, slightly soluble in alcohol, ether and acetone.

This compound is not described in the literature. PHARMACOLOGICAL STUDY OF l'-[3a-ACETOXY- Agul) 5/3 ANDROSTENE-Ufi yl] 3,5,8' TRI- OXA B ICYCLO-2,2,2-OCTANE '1. Action on the Coronary Blood Flow The study of the action of this compound on coronary blood fiow was made on the isolated rabbit heart using a technique inspired by Langendorfi (Arch. gesam. Physiol, 1895, 6 1, 291). In this method, the heart was suspended by the aorta to a canula and the coronary system was perfused, by means of this canula, under a con stant pressure of 5 cm. of mercury, with Locke serum, at a pH of 7.2 to 7.3, heated to 37 C.

The compound studied was placed in solution in ethanol and this solution was diluted with Locke serum to a convenient concentration. A 3-way stop cock permited instantaneous changing from normal Locke serum to the serum containing the product to be studied. On a proper apparatus the coronary blood flow and the ventricularly contractions were registered.

The least-concentration of this compound which clearly augments the coronary blood flow of such a preparation was systematically searched and the results obtained with this compound and with papaverine hydrochloride are shown in Table II. It is to be noted that under the same experimental conditions the minimal active concentration of papaverine hydrochloride was 10 'y/ cc. whereas the compound of the invention had a minimal active concentration situated between 0.01 and 0.05 1 /66.

At a concentration of 1 'y/cc. a 20% diminution of the frequency of cardiac beats was noted and a positive clear inotropic effect was also noted. The augmentation of the coronary blood flow attained (expressed as a percentage of the initial blood flow) was thus II. Determination of Spasmolytic Efiect on the Contracture of the Isolated Intestine of Guinea Pigs A fragment of the ileum of a guinea pig Was suspended in an isolated organ tube of 10 cc. containing constantly oxygenated Tyrode liquid maintained at 37 C. The contractures of the intestine were provoked by the addition of barium chloride, acetyl choline or histamine to the Tyrode liquid. The 1'[A -Sfi-androstene-Eta-ol-17B- yl]-3',5',8'-trioxa bicyclo-[2,2,2]-octane (A) or the 1- [30 acetoxy A901) 5,8 androstene 17B yl] 3',5,- 8'-trioxa bicyclo-[2,2,2]-octane (B) were added to the bath at the maximum of the oontracture and the minimal concentration of the compound which provoked the decontraction of the organ was determined. The minimal concentration of the compounds A and B which inhibited the action of a new dose of contracturing agent was also determined. For comparison, the same tests were conducted with papaverine hydrochloride. The results obtained are shown in Table TH attached.

TABLE III.-CONCENTRATIONS OF THE COMPO ND STUDIED EXPRESSED IN 'y/CC. OF THE BATH NEEES- SARY IN ORDER TO PRODUCE DE'CONTRACTION OF THE CONTRACTED ORGAN (D) AND INHIBITION OF THE ACTION OF THE CONTRACTURING AGENT (I) III. Determination of Spasmolytic Efiecz on Isolated Biliary Vesicule of Guinea Pigs This test was made under the conditions described by Chiray et al. (Revue du Foie, 1943, 2nd series) and by utilizing the vesicule of a guinea pig kept fasting for 24 hours. The contracture was provoked by the addition of barium chloride. 1-[A -5[3-androstene-3a-ol-17B- yl]-3',5,8-trioxa bicyclo-[2,2,2]-octane (A) used at a concentration of 1015 'y/CC. inhibited the action of this contracturing agent.

Various modifications or the process and composition of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. Compounds having the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms.

2. 1' (A 55 androstene 3a ol 17p yl) 3, 5',8-trioxa bicyclo-(2,2,2)-octane.

3. 1 (3a acetoxy A901) 5B androstene 17B yl)-3',5',8-trioxa bicyclo-(2,2,2)-octane.

4. Compounds having the formula CHzOAc wherein Ac is an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

5. 3a,21 diacetoxy 2O bis (acetoxymethyl) A -5,8-pregnene.

6. 2Q- bis (hydroxymethyl) A901) 55 pregnene 3a,21-diol.

7. A process for the preparation of compounds having the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms which comprises dehydrating a 301,211 diacyloXy 20 bis (acyloxyrnethyl) 5,8- pregnane-llfi-ol with a dehydrating agent to form a 30:, 21 diacyloxy 20 bis (acyloxymethyl) A /3 pregnene wherein the acyl radical is derived from an organic carboxylic acid having 1 to 18 carbon atoms, saponifying the latter under alkaline conditions to form 20 bis (hydroxymethyl) A901) 55 pregnene 30c, 21-diol, condensing the latter with a lower alkyl orthoformate in the presence of an acidic condensation catalyst to form 1'-(A -5fi-androstene-3a-ol-17,8-yl)-3,5', 8-trioxa bicyclo-(2,2,2)-octane and recovering a compound of the above formula.

8. The process of claim 7 wherein the dehydrating agent is selected from the group consisting of perchloric acid in acetic acid and methane sulfonyl chloride and pyridine in dimethylformamide.

9. The process of claim 7 wherein the lower alkyl orthoformate is ethyl orthoformate.

10. A process for the preparation of 1'-[A -5fi-androstene 3a-ol-17B-yl]-3',5,8'-trioxa bicycio-(2,2,2)-octane which comprises dehydrating 3a,21diacetoxy-20- bis-(acetoxymethyl)-5fi-pregnane-l15-01 with a dehydrating agent to form 30,21- diacetoXy-2O-bis-(acetoxymethyl)-A -5B-pregnene, saponifying the latter with an aqueous sodium hydroxide solution to form ZO-bis-(hydroxymethyl) A -5fi-pregnene-3a,2l-diol, condensing the latter with ethyl orthoforfate in the presence of p-toluene sulfonic acid to form 1'-(A -5fi-androstene-3a-ol- 17fl-yl)-3',5',8-trioxa bicyclo-(2,2,2)-octane and recovering the latter.

11. A process for the preparation of 1-(3u-acetoxy A901) 5/3-androstene-17B-yl)-3,5',8'-trioxa bicyclo-(2,2, 2)-octane which comprises dehydrating 3a,21-diacetoxy- 20-bis-(acetoxymethyl)-5fl-pregnane-11,8-01 with a dehydrating agent to form 3a,21-diacetoxy-20-bis-(acetoxymethyl)-A -5,8-pregnene, saponifying the latter with an aqueous sodium hydroxide solution to form 20-bis-(hydroxymethyl) A -5fl-pregnene-3a,2l-diol, condensing the latter with ethyl orthoformate in the presence of ptoluene sulfonic acid to form 1- (A -5[3-androstene- 30 ol 17/3 yl) 3,5,8 trioxa bicyclo-(2,2,2)-octane, esterifying the latter with acetic acid anhydride to form 1' (3a acetoxy A901) androstene yl) 3', 5',8-trioxa bicyclo-(2,2,2)-octane and recovering the latter.

12. A composition for the treatment of spasms of vascular and visceral origin comprising 5 to 50 mgn. of an androstene compound having the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 7 carbon atoms and a pharmaceutical carrier.

13. A composition of claim 12 wherein the androstene compound is 1-(A -5fl-androstene-3zx-ol-17fi-yl)- 3,5',8'-trioxa bicyclo-(2,2,2)-octane.

14. A composition of claim 12 wherein the androstene compound is 1'-(3a-acetoxy-A -5fi-androstene- 17B-yl)-3-,5,8-trioxa bicyclo-(2,2,2)-octane.

No references cited. 

1. COMPOUNDS HAVING THE FORMULA
 12. A COMPOSITION FOR THE TREATMENT OF SPASMS OF VASCULAR AND VISCERAL ORIGIN COMPRISING 5 TO 50 MGN. OF AN ANDROSTENE COMPOUND HAVING THE FORMULA 